UNIPROT:P04141 - FACTA Search

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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fourteen patients with relapsed Hodgkin's disease responded to a salvage therapy with Dexa-BEAM (dexamethasone, BCNU, etoposide, Ara-C and melphalan). In seven patients a continuous i.v. infusion with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was started subsequent to Dexa-BEAM (+rhGM-CSF) while the other seven patients received no hemopoietic growth factor (-rhGM-CSF). It was our objective to study the impact of rhGM-CSF on the collection of blood-derived hemopoietic stem cells in patients with extensive prior chemo- and radiotherapy not eligible for marrow harvest. Compared to baseline, we observed a significant increase of colony-forming units granulocyte-macrophage (CFU-GM) in the peripheral blood of patients receiving rhGM-CSF (p less than 0.05). On average, the yield of total nucleated cells and CFU-GM collected per single leukapheresis was 2.2 and 2.4-fold higher in the rhGM-CSF-treated patients respectively (p less than 0.05). With rhGM-CSF the interval from the start of chemotherapy to the end of blood stem cell collection could be reduced by 6 days (p less than 0.05). Following the CBV pretransplant regimen (cyclophosphamide, BCNU, etoposide), the reinfusion of rhGM-CSF-exposed stem cells resulted in a shorter time of leukocyte recovery (p less than 0.05). The number of CFU-GM/kg body weight transplanted was found to be predictive for the time of neutrophil recovery (p less than 0.05). In patients with bone marrow hypoplasia or fibrosis, rhGM-CSF as part of an effective salvage therapy improves the collection of blood stem cells that are capable of restoring hemopoiesis after high-dose pretransplant therapy.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) subsequent to chemotherapy improves collection of blood stem cells for autografting in patients not eligible for bone marrow harvest. 135 17

High dose Ara-C (HIDAC) induces programmed cell death (PCD) or apoptosis in vitro in human myeloid leukemia cells, which correlates with the inhibition of their clonogenic survival. Hematopoietic growth factors (HGFs) granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) have been demonstrated to enhance the metabolism and cytotoxic effects of HIDAC against leukemic progenitor cells. We examined the effect of pIXY 321 (a GM-CSF/IL-3 fusion protein) on HIDAC-induced PCD and related gene expressions as well as HIDAC-mediated colony growth inhibition of human myeloid leukemia cells. Unlike the previously described effects of HGFs on normal bone marrow progenitor cells, exposure to pIXY 321 alone for up to 24 hours did not suppress PCD in HL-60 or KG-1 cells. However, exposure to pIXY 321 for 20 hours followed by a combined treatment with Ara-C plus pIXY 321 for 4 or 24 hours versus treatment with Ara-C alone significantly enhanced the oligonucleosomal DNA fragmentation characteristic of PCD. This was temporally associated with a marked induction of c-jun expression and a significant decrease in BCL-2. In addition, the treatment with pIXY 321 plus HIDAC versus HIDAC alone produced a significantly greater inhibition of HL-60 colony growth. These findings highlight an additional mechanism of HIDAC-induced leukemic cell death that is augmented by cotreatment with pIXY 321 and may contribute toward an improved antileukemic activity of HIDAC.
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PMID:Granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein (pIXY 321) enhances high-dose Ara-C-induced programmed cell death or apoptosis in human myeloid leukemia cells. 145 Apr 13

Freshly isolated human mononuclear cells (5 x 10(6)) were incubated in a Dexter-type long-term bone marrow culture (LTBMC) system to study myelosuppressive effects of cytosine arabinoside (Ara-C) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin 3 (IL-3). Differential counts (dc) of the nonadherent cell (nac) populations, starting with culture initiation, were performed weekly. After one week of simultaneous incubation of LTBMCs with either cytokine (100 ng/ml) and Ara-C (1 microgram/ml), nac numbers were markedly reduced compared to controls. Dc after week 1 of culture demonstrated significant decreases of all myeloid cell fractions except for macrophages, which remained unaffected. Growth factor-dependent LTBMCs exposed to Ara-C showed recovery of promyelocytic, metamyelocytic, and polymorphonuclear cell numbers up to control values (cultures without Ara-C exposure) in weeks 3 to 6. Intriguingly, high-proliferative, early myeloid progenitor cells (myeloblasts) appeared at high rates only in IL-3-dependent LTBMCs with and without Ara-C exposure. Nac numbers in LTBMCs exposed to Ara-C alone declined rapidly; after two weeks of culture only negligible numbers of viable nac were maintained. Plating experiments of nac in the presence of GM-CSF were performed weekly. Granulocyte-macrophage colony-forming units (CFU-GM) yields for nac from IL-3 LTBMCs were consistently higher than those for nac from GM-CSF LTBMCs. Ara-C exposure reduced CFU-GM numbers generated with nac from GM-CSF LTBMCs to 10% of GM-CSF controls (week 1). However, CFU-GM numbers grown with nac from Ara-C exposed GM-CSF-dependent LTBMCs recovered above control levels after week 3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myelosuppressive effects of cytosine arabinoside (Ara-C) on growth factor-dependent human long-term bone marrow cultures (LTBMC). 155 25

Hematopoietic growth factors (HGFs) interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) individually have been shown to increase the percentage of acute myeloid leukemia (AML) blasts in S phase and enhance the cytotoxic effects of Ara-C against these blasts in culture. We compared in vitro the effects of a combined treatment with GM-CSF (10 ng/mL) plus IL-3 (10 ng/mL) on the metabolism and cytotoxicity of Ara-C in normal bone marrow mononuclear cells (NBMMC) and AML blasts. NBMMC from six healthy volunteers and AML blasts from 10 patients were incubated for 20 hours with or without IL-3 plus GM-CSF, followed by a concurrent treatment with Ara-C for 4 additional hours. Exposure to the HGFs and Ara-C produced significantly higher intracellular Ara-CTP levels as well as higher Ara-CTP/dCTP pool ratios in AML blasts as compared with NBMMC. Treatment with HGFs resulted in [3H] Ara-C DNA incorporation that was significantly higher in AML blasts versus NBMMC. This selective improvement of Ara-C metabolism in AML blasts was associated with an enhanced Ara-C-mediated leukemia colony-forming unit (CFU) growth inhibition. In contrast, exposure to HGFs resulted in an improved colony growth of normal CFU granulocyte-monocyte and CFU-granulocyte, erythroid, monocyte, megakaryocyte. These in vitro studies indicate that a combined treatment with IL-3 plus GM-CSF may improve the selectivity of Ara-C against AML blasts.
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PMID:Treatment with interleukin-3 plus granulocyte-macrophage colony-stimulating factors improves the selectivity of Ara-C in vitro against acute myeloid leukemia blasts. 182 60

Based on in vitro data suggesting that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is capable of stimulating acute myeloid leukemia (AML) blast cells to become more sensitive to cell-cycle-specific drugs we conducted a phase I/II study in de novo AML patients (pts). rhGM-CSF (250 micrograms/m2/d, continuous intravenous infusion) was administered in 18 pts suffering from de novo AML in combination with standard induction chemotherapy (3 + 7 = daunorubicin 45 mg/m2 days 1 through 3, cytosine-arabinoside [Ara-C] 200 mg/m2 continuous infusion days 1 through 7). GM-CSF was started 48 or 24 hours before chemotherapy (prephase) in 14 pts. In four pts with high white blood cell counts (WBC) rhGM-CSF was started after chemotherapy-induced cell reduction (WBC less than 30,000/mm3). During prephase GM-CSF induced an increase in neutrophil and blast cell counts in 13 of 14 and 10 of 14 pts, respectively. In vivo recruitment of leukemic cells into drug-sensitive phases of the cell cycle could be demonstrated by multiparameter cell-cycle analyses in peripheral blood (n = 7) and bone marrow (n = 4) specimens. On day 14, complete aplasia was evident in 17 of 18 pts. GM-CSF was administered until recovery from chemotherapy-induced myelosuppression (absolute neutrophil counts, [ANC] greater than 500/mm3). Fifteen pts (83%) achieved complete remission, 12 did so with one cycle. A shorter duration of neutropenia was evident in these pts compared with historical controls (n = 39), (ANC greater than 500/mm3, day 22.5 +/- 3.4 v 25.2 +/- 3.7, P less than .05). Three pts achieved complete remission after a second cycle (same combination of rhGM-CSF and 3 + 7). Two pts died during bone marrow aplasia because of invasive pulmonary aspergillosis. Clinical side effects possibly related to GM-CSF, mainly fever, diarrhea, and weight gain were mild and tolerable (World Health Organization toxicity grade less than or equal to 2). Together, rhGM-CSF recruits kinetically quiescient AML cells in vivo to enter drug-sensitive phases of the cell cycle and promotes early myeloid recovery from aplasia after exposure to standard induction chemotherapy for AML.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia. 199 13

We investigated the cytotoxic effect of the cell cycle-specific agent cytosine arabinoside (Ara-C) on clonogenic leukemic and normal bone marrow cells. To overcome kinetic resistance and to increase cytotoxicity, the cells were exposed to Ara-C in liquid culture medium for extended time periods, that is, 5 and 10 days. Subsequently the number of surviving clonogenic cells was determined in a semi-solid assay. All cultures were stimulated with the combination of recombinant human interleukin 3 (rhIL-3), granulocyte-macrophage colony-stimulating factor (rhGM-CSF), and granulocyte colony-stimulating factor (rhG-CSF) to induce optimal cell proliferation. In comparison to normal clonogenic bone marrow cells (granulocyte-macrophage colony-forming units, CFU-GM) 5-day Ara-C exposure resulted in an equal to a slightly more effective kill of leukemic colony-forming cells (CFU-L). The Ara-C dose resulting in 50% inhibition (ID50) was 1.6 +/- 1.6 x 10(-8) M for CFU-L (n = 9) and 6.7 +/- 4.3 x 10(-8) M for CFU-GM (n = 4, p = 0.096). Prolongation of the Ara-C exposure time from 5 to 10 days increased the cytotoxicity towards the majority of the leukemic clonogenic cells (ID50: 0.8 +/- 0.6 x 10(-8) M) but not towards CFU-GM (ID50: 5.7 +/- 2.8 x 10(-8) M). Overall, significantly more leukemic clonogenic cells than normal CFU-GM were killed after 10 days of exposure to Ara-C (p = 0.039). These results indicate that leukemic clonogenic cells can be eradicated preferentially by prolonged exposure to low dosages of Ara-C in the presence of hematopoietic growth factors with relative preservation of the normal hematopoietic progenitor cells.
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PMID:Prolonged exposure to cytosine arabinoside in the presence of hematopoietic growth factors preferentially kills leukemic versus normal clonogenic cells. 156 52

To investigate effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on lymphoid cells in vivo, we monitored changes in absolute lymphocyte counts, plasma concentrations of soluble interleukin-2 receptor (sIL-2R) and soluble cytotoxic/suppressor (sCD8) antigens, and phenotypic changes of surface membrane antigens of peripheral mononuclear cells from 14 patients with malignant lymphoma treated with rhGM-CSF. Eight of the 14 patients had relapsed or had refractory non-Hodgkin's lymphoma (NHL) and received rhGM-CSF after intensive chemotherapy with novantrone (NO) and high-dose Ara-C (AC) (NOAC) as salvage regimen. Six other patients with NHL or Hodgkin's disease (HD) were in complete remission and treated with rhGM-CSF to enhance peripheral hematopoietic progenitor cell harvest for autografting. An increase in absolute lymphocyte count at the zenith of leukocyte elevation and a drastic increase in concentration of sIL-2R from a median of 565 U/mL to 6,700 U/mL on rhGM-CSF infusion were found in all patients. There was also a moderate increase in sCD8 levels from a median of 277 U/mL to 470 U/mL. Ten patients were available for serial studies of phenotypic changes in surface membrane antigens. A significant increase in CD25+ (IL-2R+) (P = .0020) and CD4+ (P = .0137) lymphocytes was observed in all patients, but no significant change in CD3+, CD8+, TCR delta 1+, or CD19+ cells. Elevations in absolute lymphocyte counts or in concentrations of sIL-2R or sCD8 were not observed in four other patients during recovery from intensive chemotherapy without rhGM-CSF support. Our results provide evidence that administration of rhGM-CSF might activate lymphocytes in vivo. The impact of this activation on the remission rate and duration, as well as survival in patients with NHL, warrants further investigation.
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PMID:Activation of lymphocytes induced by recombinant human granulocyte-macrophage colony-stimulating factor in patients with malignant lymphoma. 210 62

Previous study has shown that the combination of mitoxantrone (Novantrone, NO) and Ara-C (AC) (NOAC) was active in refractory non-Hodgkin's lymphoma (NHL) but myelosuppression was dose-limiting. In a pilot study, we investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) after NOAC chemotherapy in patients with refractory NHL. NO was applied at a dosage of 10 mg/m2/day on days 2 and 3 and AC at 3 g/m2/12h on days 1 and 2. RhGM-CSF was administered at 250 ug/m2/day as a continuous i.v. infusion from day 6 until the neutrophils were greater than 3.0/nl for 3 consecutive days. Twenty-three patients from five of the nine participating centers were treated with NOAC chemotherapy plus rhGM-CSF, whereas 14 patients from the other four centers received chemotherapy alone. With rhGM-CSF, the median duration of severe neutropenia (less than 0.5/nl) after NOAC was 8 days versus a median of 13 days without rhGM-CSF (P = 0.0058), and that of thrombocytopenia (less than 20.0/nl), 3 days versus 7 days (P greater than 0.4, NS). The rates of infections and stomatitis were 25% and 17%, respectively, for patients treated with rhGM-CSF as compared to 53% (P = 0.0547, NS) and 60% (P = 0.0078), respectively, without rhGM-CSF. The following side effects were associated with the administration of rhGM-CSF: pleural and/or pericardial effusions in five patients, thrombosis in two patients, bone pain in two patients, and respiratory distress syndrome in one patient. A complete remission was achieved in nine of the 23 patients treated with NOAC plus rhGM-CSF, and in two of the 14 patients treated with chemotherapy alone. The median survival of patients treated with rhGM-CSF was not reached at 400 days and seemed to be longer than that of patients treated with chemotherapy alone (median, 109 days; P = 0.036). RhGM-CSF after chemotherapy can be applied safely to patients with NHL, shorten the period of severe cytopenia, reduce the rates of stomatitis, and did not seem to cause adverse effects on response.
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PMID:Mitoxantrone/high-dose Ara-C and recombinant human GM-CSF in the treatment of refractory non-Hodgkin's lymphoma. A pilot study. 219 41

Mitoxantrone (Novantrone, American Cyanamid Company; NO) and high-dose cytarabine (Ara-C; AC) have each been shown to be active in non-Hodgkin's lymphomas (NHL) in various studies. The studies reported here are sequential. The first study (NOAC I) combined high-dose cytarabine (3 g/m2/12 h as a 3 h infusion on day 1) with mitoxantrone (10 mg/m2/d on days 2 and 3). Of 31 patients with relapsed and refractory NHL, 7 achieved complete remission (CR) and 7, partial remission (PR). Myelosuppression was the major toxicity of this regimen. In the second study (NOAC II), the dosage of cytarabine was escalated to 3 g/m2/12 h on days 1 and 2 (4 doses) while mitoxantrone remained 10 mg/m2/d on days 2 and 3. The effects of recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-CSF) were simultaneously studied. Twenty-three patients from five centers were treated with NOAC plus rhGM-CSF while 14 patients from four centers received NOAC II alone. A CR was achieved in 9 of 23 patients who received the additional rhGM-CSF and in 2 of 14 patients treated with NOAC alone. With rhGM-CSF, the median duration of severe neutropenia (less than 0.5/nL) after chemotherapy was 8 days versus a median of 13 days without rhGM-CSF, while the duration of severe thrombocytopenia (less than 20/nL) was not significantly different. The rates of infection and mucositis were 25% and 17%, respectively, with rhGM-CSF compared to 53% and 60% without rhGM-CSF. Thus, this last nonrandomized pilot study indicates that administration of rhGM-CSF reduces the duration of chemotherapy-induced cytopenia and the rate of mucositis. This growth factor does not appear to result in stimulation of lymphoma cells. At present, a controlled randomized trial is being conducted using NOAC II with rhGM-CSF or placebo to establish the definitive role of this growth factor in the treatment of NHL.
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PMID:Sequential studies on the role of mitoxantrone, high-dose cytarabine, and recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of refractory non-Hodgkin's lymphoma. 225 18

Laboratory studies have suggested that hematopoietic growth factors (GF), combined with cytosine-arabinoside (Ara-C) can enhance cytotoxic effects of this agent against acute myeloid leukemia (AML) cells. While clinical trials based on this growth factor/chemotherapy combination (GF/CT) are progressing with discordant results, further information regarding the underlying mechanisms have been reported supporting this rationale and requiring additional investigation. To assess the role of cytokinetic changes in the GF/CT strategy and to evaluate if chemotherapeutic agents regimens other than Ara-C, when combined with GF, can enhance their cytotoxic effects, we have primed AML blasts with two cytokine combinations and then exposed these cells to the S-phase specific agent Ara-C as well as to the phase non-specific drug daunorubicin (DNR) and to the alkylating agent 4-hydroperoxycyclophosphamide (4-HC). The two cytokine combinations used for priming AML blasts were: (i) interleukin-3 (IL-3) + granulocyte-macrophage colony-stimulating factor (GM-CSF) + granulocyte colony-stimulating factor (G-CSF); and (ii) GM + G-CSF. Cytokinetic analysis in ten AML samples and clonogenic growth of leukemic colonies (CFU-L) in methylcellulose were used to detect proliferative and cytotoxic effects on AML samples. We report that in AML clonogenic cell growth can be stimulated by cytokines in 50% of the samples (4/8), and that Ara-C sensitization clearly occurs in two out of these four samples. Among the different cytokine combinations tested, the one containing IL-3 was the most effective through a cytokinetic mechanism consistent with recruitment (averaged G0 decrease p = 0.04; S-phase increase p = 0.005). Furthermore we observed increased cytotoxicity also to the phase non-specific drugs DNR and 4-HC, which may be mediated by other mechanisms recently described. We conclude that GF/CT combinations may also be beneficial in regimens containing drugs other than Ara-C, used for AML treatment, including bone marrow transplantation conditioning regimens.
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PMID:Combination of hematopoietic growth factors containing IL-3 induce acute myeloid leukemia cell sensitization to cycle specific and cycle non-specific drugs. 751 44

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